SIPI-2011

SIPI-2011, a structural modification of isoquinoline alkaloid, is under investigation for treating arrhythmias. To characterize the safety and tolerability, the pharmacokinetics and metabolism of SIPI-2011 were investigated in humans. After an oral administration of 600 mg SIPI-2011, a total of 32 metabolites were detected in human plasma by UPLC-UV/Q-TOF mass spectrometry utilizing mass defect filter method. The principal biotransformation pathways included di-dehydrogenation (M8-1), dehydrogenation (M9-2), and oxidation and dehydrogenation (M10-4). Afterward, a sensitive LC-MS/MS method was developed to simultaneously determine SIPI-2011 and its two major metabolites M8-1 and M9-2 in human plasma. The isotopically labeled internal standards of the metabolites were obtained by incubating deuterated SIPI-2011 with rat liver homogenates. To achieve effective chromatographic retention and separation, three analytes were eluted on an XDB-phenyl column with alkaline mobile phase, and detected by multiple reaction monitoring (MRM) with positive electrospray ionization source. To reduce the interference from the isotope signals of M8-1 and M9-2 in the higher calibration point, [M+H+ 1]⁺ ions were selected as precursor ions of M9-2 and SIPI-2011 for MRM analysis. The assay was linear in the concentration range 15.0-3000 ng/mL for SIPI-2011, 0.500-100 ng/mL for M8-1 and 1.00-200 ng/mL for M9-2. The parameters of the method validation all met the acceptance criteria. The pharmacokinetic study indicated that SIPI-2011 was rapidly absorbed with a median T_max of 0.65 h and a terminal half-life of 15.4 h when healthy volunteers were administered a single dose of 300 mg SIPI-2011. And the plasma exposures of the two metabolites M8-1 and M9-2 were less than 10 % of that of the parent drug.